Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:24][CH2:25][C:26](=[O:40])[CH2:27][CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:48]1([CH3:57])[CH:53]=[CH:52][C:51]([C:54](Cl)=[O:55])=[CH:50][CH:49]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:25][C:26](=[O:40])[CH2:27][CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39])[C:54](=[O:55])[C:51]1[CH:52]=[CH:53][C:48]([CH3:57])=[CH:49][CH:50]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)C(NCC(=O)CCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CC(=O)CCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 42.8 %

Procedure:
A solution of 2-{4-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-3-oxo-butyl}-isoindole-1,3-dione (1.5 g from previous step), triethylamine (245 mg, 2.42 mmol), and p-toluoyl chloride (374 mg, 2,42 mmol) in methylene chloride (10 mL) was stirred at room temperature for 2.0 h. The reaction was washed sequentially with 0.5 N HCl, water, 5% NaHCO3, water, and brine and dried (Na2SO4). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel 3:2 hexanes:EtOAc as eluent) to provide the title compound as a white solid (0.7 g, 35%, 2 steps). MS(ES+) m/e 675 [M+H]+.
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([I:43])=[CH:29][N:30]2[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:26][C:25]=1[C:44]([OH:46])=O.NN>O.CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([I:43])=[CH:29][N:30]2[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:26][C:25]=1[C:44]([NH:7][NH2:8])=[O:46]
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)c(F)cc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 245.2 %

Procedure:
HOBt (Aldrich, St. Louis, Mo., 303 mg, 2.24 mmol), EDC HCl (430 mg, 2.242 mmol) and 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carboxylic acid (858 mg, 1.87 mmol) were weighed into a 250 mL round bottomed flask and treated with DMF (7 mL). The resulting solution was stirred at RT for 30 min. The reaction mixture was then treated with anhydrous hydrazine (0.29 mL, 9.34 mmol) and stirred at RT for 30 min. The reaction mixture was diluted with water resulting in precipitate formation. The solid was collected by filtration, washed with water, and dried under high vacuum for 3 h at 50° C., affording crude 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (2.17 g) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 473.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.59 (1H, br. s.), 8.17 (1H, s), 8.01 (2H, d, J=8.4 Hz), 7.97 (5H, s), 7.82 (1H, d, J=10.8 Hz), 7.50 (1H, d, J=6.5 Hz), 7.45 (3H, d, J=8.2 Hz), 4.56 (2H, br. s.), 4.11 (3H, br. s.), 2.36 (4H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH:16]([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[CH:3][CH:2]=1.O.[NH2:21][NH2:22]>C(O)(C)C>[CH3:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:21][NH:22][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:8]2[CH2:17]1
Reactant: CC1CC(=Cc2ccncc2)C(=O)c2ccccc21
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC1Cc2c(n[nH]c2-c2ccncc2)-c2ccccc21

Procedure:
To 24.0 grams (0.1 oles) of the compound of Step A of this exampel in a flask equipped with stirrer and condenser are added 4.8 grams (0.15 Mole) of hydrazine hydrate (95%) and 150 ml. of isopropanol. The mixture is stirred and refluxed for about 24 hours and the solvent is then crystallized from methanol to given 4,5-dihydro-5-methyl-3-(4-pyridyl)-2h-naphtho[1,2-c]pyrazole.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23]C)=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30]Cl.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[NH2:25][C:16]1[N:15]=[C:14]([O:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])[N:22]=[C:21]2[C:17]=1[NH:18][C:19](=[O:23])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNCC1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 19 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1-bromo-4-chlorobutane and piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:7][C:6]2=[S:22].[I:23][CH3:24]>>[I-:23].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N+:9]([CH3:15])=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:7]=[C:6]2[S:22][CH3:24]
Reactant: COc1cc2c(=S)nc(-c3ccccc3)n(C)c2cc1OC
Reactant: CI
Product: COc1cc2c(SC)nc(-c3ccccc3)[n+](C)c2cc1OC
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (3.20 mmol) 6,7-Dimethoxy-1-methyl-2-phenyl-1H-quinazolin-4-thione was slowly added to 5 ml (80 mmol) iodomethane at 0° C. and stirred for 1 h at room temperature. The solution was filtrated and the residue washed with ethyl ether and dichloromethane.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH:15]([CH2:18][F:19])[CH2:16][F:17])[CH2:10]1)(C)(C)C.Cl>O1CCOCC1>[F:19][CH2:18][CH:15]([N:11]1[CH2:12][CH2:13][O:14][CH:9]([CH2:8][NH2:7])[CH2:10]1)[CH2:16][F:17]
Reactant: CC(C)(C)OC(=O)NCC1CN(C(CF)CF)CCO1
Agent: Cl
Solvent: C1COCCO1
Product: NCC1CN(C(CF)CF)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 252A (538 mg) in dioxane (4 mL) was treated with 4.0M HCl in dioxane solution (1.8 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and used without further purification.
Reaction SMILES: [CH2:1]([C:8]1([N:16]([CH3:18])[CH3:17])[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([Cl:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH2:1]([C:8]1([N:16]([CH3:18])[CH3:17])[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].[CH2:1]([C:8]1([N:16]([CH3:18])[CH3:17])[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC1CCC(Cc2ccccc2)(N(C)C)CC1
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1)C1CCC(Cc2ccccc2)(N(C)C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.00 g 1-benzyl-N,N,N′-trimethyl-cyclohexane-1,4-diamine were dissolved in 50 ml methylene chloride, and 1.78 ml triethylamine and approx. 10 mg DMAP were added. 1.41 ml benzoyl chloride were added dropwise, while cooling in an ice/methanol bath, and the reaction mixture was then stirred overnight, while warming to room temperature. For working up, 50 ml five molar KOH solution and 50 ml water were added, the mixture was stirred for ten minutes and extracted three times with 50 ml methylene chloride each time, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. The crude product obtained (3.61 g) was chromatographed over silica gel with methanol/ether 1:1. 231 mg of the polar diastereomer of N-(4-benzyl-4-dimethylamino-cyclohexyl)-N-methyl-benzamide were obtained, from which 188 mg of the corresponding hydrochloride were prepared as described for example 1 with water and chlorotrimethylsilane in 2-butanone.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=2)=[O:18])=[O:7])=[C:28]([CH3:35])[CH:27]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Reactant: NCCc1cccc(O)c1
Product: CON=C1C[C@@H](C(=O)NCCc2cccc(O)c2)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1-biphenyl]-4carboxylic acid, and 3-(2-aminoethyl)phenol, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.N1C=CC=CC=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][C@H:31]([NH:35][C:36](=[O:62])[C@H:37]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=2)[NH:38][C:39](=[O:53])[CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:32]([NH2:34])=O)[CH:25]=[CH:26][CH:27]=1)=[O:21]>CCOC(C)=O>[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][C@H:31]([NH:35][C:36](=[O:62])[C@H:37]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=2)[NH:38][C:39](=[O:53])[CH:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:32]#[N:34])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: COC(=O)c1cccc(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(N)=O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CCC[C@@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.12 mL, 1.39 mmol) is added dropwise to DMF (10 mL), and the resulting solution is cooled to 0° C. After the solution is clear, pyridine (0.22 mL, 2.78 mmol) is added, followed by N-[4-(3-methoxycarbonylphenyl)-1(S)-(aminocarbonyl)butyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide (0.42 g, 0.70 mmol), in one portion. The yellow reaction solution is stirred at 0° C. for 1.5 hours, after which time it is diluted with EtOAc (50 mL), and washed with saturated aqueous NaHCO3 solution (1×50 mL), saturated aqueous LiCl solution (1×50 mL), dried over MgSO4, and evaporated. The residue is chromatographed to yield N-[4-(3-methoxycarbonyl-phenyl)-1(S)-cyanobutyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide, as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[C:13](=[O:35])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.O.Cl>O1CCOCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][OH:23])=[O:21])[C:13](=[O:35])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
4-[4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (220 mg, 0.429 mmole) was dissolved in dioxane (4 ml), DCM (4 ml) and water (2 ml). To this was added a 4.0M solution of HCl in dioxane (1.0 ml, 4.29 mmole) and was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and azeoptroped with IPA (2×5 ml) to afford a white solid (100 mg, 54.4%). MS (LC/MS) m/z 429.1 (M+1)1H NMR (400 MHz, METHANOL-d4) δ ppm 0.83-1.06 (m, 3H) 1.19-1.40 (m, 6H) 1.41 (s, 2H) 1.64-1.90 (m, 4H) 2.31-2.41 (m, 1H) 2.61-2.79 (m, 1H) 3.08 (s, 3H) 3.60 (s, 1H) 3.63-3.71 (m, 1H) 3.86-3.99 (m, 2H) 4.04 (s, 1H) 4.11 (d, J=8.00 Hz, 3H) 4.25-4.41 (m, 1H) 6.29 (s, 1H) 6.53-6.68 (m, 1H) 7.83-7.93 (m, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[NH:4][N:3]=1.O.[CH:23]([NH2:25])=O>>[NH2:8][C:7]1[N:25]=[CH:23][N:1]=[C:2]2[NH:3][N:4]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:11][CH:10]=3)[C:6]=12
Reactant: N#Cc1c(N)n[nH]c1-c1ccc(Oc2ccccc2)cc1
Reactant: NC=O
Solvent: O
Product: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 180 °C

Procedure:
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (29.5 g) is suspended in formamide (300 mL) and heated under nitrogen at 180° C. for 4 hours. The reaction mixture is cooled to 30° C. and water (300 mL) is added. The solid is collected, washed well with water, then with methanol and dried in air to give of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>[Pd].C(O)C>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1C
Yield: 97.5 %

Procedure:
In the presence of 0.1 gram of 5% palladium on carbon, a solution of 14.0 grams (0.072 mole) of methyl 2-methyl-3-nitrobenzoate in 100 mL of ethanol was hydrogenated using a Parr hydrogenator, yielding 11.6 grams of subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was run several times.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: OCc1cccc(CBr)c1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(CO)c3)C(C)(C)C2=O)cn1
Yield: 70 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and (3-(bromomethyl)phenyl)methanol. Yield 70%, white solid. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.47 (d, J=6.0 Hz, 2H), 4.54 (s, 2H), 5.15 (t, J=5.6 Hz, 1H) 5.2 (s, 2H), 7.25 (m, 3H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCCC1.[H-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][C:34]([N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:35])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Yield: 53.9 %

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (2.0 mg, 60% oil dispersion) in one portion at 5° C. The mixture was stirred for half an hour at the same temperature and then morpholinocarbonyl chloride (6.8 mg) was added thereto. The reaction mixture was stirred for 2 hours at ambient temperature and diluted with diethyl ether (2 ml). The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane=2/1) to yield 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (9.7 mg) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][C:6]=1[NH:18][C:19](=[O:37])[CH2:20][CH:21]([C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[O:35][CH3:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CCCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][C:6]=1[NH:18][C:19](=[O:37])[CH2:20][CH:21]([C:27]1[C:28]([O:35][CH3:36])=[CH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CCC(=O)OCC)ccc1C(C)(C)C)c1c(OC)cccc1OC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)O)ccc1C(C)(C)C)c1c(OC)cccc1OC

Procedure:
Following a similar procedure to that described in Preparation 77, but using N-[2-t-butyl-5-(2-carboethoxyethyl)phenyl]-3-(2,6-dimethoxyphenyl)octanamide (prepared as described in Preparation 86), the title compound was obtained as colorless crystals, melting at 52-53° C. (from methylene chloride-hexane).
Reaction SMILES: CC1(C)N(CCCCCCCCCS(CCCC(F)(F)C(F)(F)F)=[O:17])C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O.[CH3:44][C:45]1([CH3:81])[N:49]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][S:55][CH2:56][CH2:57][CH2:58][C:59]([F:65])([F:64])[C:60]([F:63])([F:62])[F:61])[C:48](=[O:66])[N:47]([C:67]2[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[C:69]([C:76]([F:79])([F:78])[F:77])[CH:68]=2)[C:46]1=[O:80]>>[CH3:44][C:45]1([CH3:81])[N:49]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][S:55]([CH2:56][CH2:57][CH2:58][C:59]([F:64])([F:65])[C:60]([F:63])([F:62])[F:61])=[O:17])[C:48](=[O:66])[N:47]([C:67]2[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[C:69]([C:76]([F:79])([F:78])[F:77])[CH:68]=2)[C:46]1=[O:80]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCS(=O)CCCC(F)(F)C(F)(F)F

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 4 replacing the compound of Example 1. 136 mg of a white solid is obtained (73%). Melting point: 95-96° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][C:28](=[O:30])[CH3:29])[C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1)(C)(C)C.Cl>O1CCOCC1>[C:22]1([CH3:26])[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:15]2[N:14]=[C:13]([C:10]3[S:9][C:8]([NH:7][CH2:27][C:28](=[O:30])[CH3:29])=[CH:12][CH:11]=3)[CH:18]=[CH:17][N:16]=2)[CH:21]=1
Reactant: CC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2ccnc(Nc3cccc(C)c3)n2)s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)CNc1ccc(-c2ccnc(Nc3cccc(C)c3)n2)s1
Yield: 10.6 %

Procedure:
(2-Oxo-propyl)-[5-(2-m-tolylamino-pyrimidin-4-yl)-thiophen-2-yl]-carbamic acid tert-butyl ester (0.078 mmol) was treated with 1 mL 4N HCl in dioxane. After 1½ hours, the mixture was concentrated in vacuo and redissolved in EtOAc. The organics were washed with saturated NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by prep LCMS to afford title compound (2.8 mg, 10.5% yield for 2 steps). %). MS: m/z 339 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ2.15 (s, 3H), 2.318 (s, 3H), 4.077 (d, J=5.5 Hz, 2H), 5.94 (d, J=4 Hz, 1H), 6.73 (d, J=8 Hz, 1H), 7.02 (d, J=5.5 Hz, 1H), 7.13 (t, J=8 Hz, 1H), 7.41 (t, J=6 Hz, 1H), 7.52 (br d, J=9 Hz, 1H), 7.59 (d, J=4 Hz, 1H), 7.75 (br s, 1H), 8.19 (d, J=5.5 Hz, 1H), 9.27 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]([OH:18])[CH3:17])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH:28]([C:31]1[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[S:43](Cl)(=[O:45])=[O:44])([CH3:30])[CH3:29].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([C:31]1[CH:36]=[C:35]([CH:37]([CH3:38])[CH3:39])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[S:43]([O:18][CH:16]([C:13]1([OH:15])[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[O:10])[CH2:12]1)[CH3:17])(=[O:44])=[O:45])[CH3:29]
Reactant: CC(O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)OC(C)C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Reaction time: 3 h
Yield: 48.8 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol (267 mg, 0.543 mmol), was dissolved in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (80 mg, 0.661 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) at ambient for 15 h. Triethylamine (0.076 mL, 0.545 mmol) was added and the mixture was stirred at ambient for 3 h and then at 35° C. for 4 h and then at ambient for a further 15 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (110 mg, 0.363 mmol) was added and the mixture was stirred at 35° C. for 3 h and then 4-(dimethylamino)pyridine (80 mg, 0.661 mmol) was added and the mixture was stirred at 35° C. for 2 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) was added and the mixture was stirred at 35° C. for a further 18 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 30-50% ethyl acetate in hexanes) to give 1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (201 mg, 0.265 mmol, 49% yield): MS (EI) for C33H38F3IN2O5S: 759 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCc1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)C(CN)c2cccc(Br)c2)cc1
Reaction time: 16 h
Yield: 68.4 %

Procedure:
3-Bromophenylethylamine hydrochloride (9.44 g) was added to THF (60 ml) containing triethylamine (12.24 ml) and stirred-under argon at 5° C. during the portionwise addition over 15 minutes of 4-methylphenylsulphonyl chloride (11.44 g). The slurry was diluted with THF (50 ml) and stirred for 16 h. The solid was filtered off, washed with THF and the filtrate evaporated. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, water, brine and dried (MgSO4). Chromatography on flash silica, eluting with 0 to 25% ethyl acetate in isohexane gave the product (9.67 g).